Proposed is a collaboration of UCSD sleep disorders and genetics investigators with the NHLBI PGA Analytical Genomics Center in Tucson. In circadian rhythm sleep disorders (CRSD), the patient's preferred sleeping time is malsynchronized with the sleep phase controlled by the circadian system. The CRSD arise partly from genetic variants in circadian system genes. Nevertheless, in humans, relatively little is known about the nature and prevalence of functional sequence variations in the genes which might produce CRSD susceptibility, nor have epistatic interactions been studied. A total of 200 evening-type patients will be recruited according to the Horne-Ostberg scale plus strict inclusion and exclusion criteria. Each patient's phenotype will be characterized by clinical data, questionnaires, and a 2-week recording of wrist activity to objectively determine sleep timing. Then 200 controls will be selected, matched to cases by age, gender, and ethnicity. Blood samples will be drawn to immortalize lymphoblastoids for DNA preservation. An additional sample of 92 Scandinavian subjects will also be used. From DNA of 40 evening-type patients, the sequences of exons and adjacent promoter and intronic regions will be determined for 10 circadian system genes. SNPs and other variants will be discovered, published in the NCBI dbSNP data base, and tabulated. The variants will then be genotyped in all 200 CRSD patients, 200 matched controls, and the Scandinavian sample, to recognize associations of CRSD with particular SNP alleles, haplotypes, and epistatic interactions. This proposal is likely to identify many of the common variants in the major genes of the human circadian system. Moreover, understanding more about the phenotypes and genetic causes of CRSD will lead to clinical diagnostic methods for CRSD, progress toward alleviating suffering due to genetic susceptibilities, and increased basic science understanding of the circadian system.